Active substances which are to be administered topically by inhalation are usually inhaled orally. If this method proves not to be directly suitable on account of particular qualities of the active substance or special requirements as to its administration, other suitable measures specific to the active substance and excipient must be taken for technical purposes, so that as a function of the physico-chemical properties of the substance a stable product can be produced in an industrially reproducible manner. For substances whose breakdown characteristics in solution prove to be critical, powder inhalation is one option. Not only does the absolute amount of this active substance which has to be administered in one application make particular demands of the formulation, but also the physical stability (e.g. aerodynamic particle size, dispersibility, physico-chemical properties) of the micronised active substance turns out to be a critical prerequisite for the development and manufacture of a powder inhalant.
In the form of powder inhalants, inhalable powders packed into suitable capsules (inhalettes), for example, are delivered using powder inhalers. There are also other known systems in which the quantity of powder to be administered is pre-metered (e.g. blisters), and also multidose powder systems. Alternatively substances may be inhaled by the use of suitable inhalable aerosols in powder form which are suspended, for example, in HFA134a, HFA227 or mixtures thereof as propellant gas.
Usually, powdered inhalants, e.g. in the form of capsules for inhalation, are prepared on the basis of the general teaching as described in DE-A-179 22 07. Another significant aspect in the development of powdered inhalants is that when the active substance is administered by inhalation only particles of a particular aerodynamic size reach the target organ, the lungs. The particle size of these lung-bound particles (inhalable fraction) is in the region of a few μm, typically between 1 and 10 μm, preferably less than 6 μm. Such particles are usually produced by micronisation (e.g. air-jet grinding).
It has become apparent that the optimisation of powdered inhalants, inter alia, can only be achieved by selecting, from the lactoses on the market, the one which is most suitable for the desired product qualities, depending on the characteristics of the active substance. Lactose producers supply a range of qualities depending on the particular requirements, for example. To improve the product qualities of powdered inhalants various possibilities have been suggested in the mean time as to how commercially obtainable lactoses can be modified and tailored to special requirements within the scope of product manufacture (e.g.: DE 4140689).
However, it has also been shown that the morphological and crystalline properties (primarily on the surface of the particles) of the lactose used contribute significantly to the product qualities.
Powdered inhalants as prepared according to the prior art (for example DE-A-179 22 07), in addition to the chemical stability of the active substance and the composition of the medicament as such must above all have physically constant properties. This means specifically that the aerosol properties must remain constant in terms of their aerodunamic characteristics (e.g. aerodynamic particle size). This means that both for the micronised active substance and for the excipients used in the product the latter should be used in their most physico-chemically stable form. For lactose, this means, from a thermodynamic point of view, that this is true when it is in the form of alpha-lactose monohydrate under normal conditions. This is particularly true of the crystalline ordering of the surface of the particles.
It is known that when organic substances are ground, as a result of the significant input of mechanical energy, amorphous fractions may be produced or there may be changes in the crystalline structure leading to thermodynamically less stable modifications. It is also known that lactose may occur in various forms (Coenraad F. Lerk, Physikalisch-pharmazeutische Eigenschaften von Lactose, Pharmazie in unserer Zeit, 16, 1987, No. 2; 39-46).
For example amorphous lactose produced during the grinding of lactose or under other mechanical stress may be recrystallised by known technical methods (e.g. WO 92/18110 or WO 95/05805). However, these methods have the drawback that they only achieve breakdown of amorphous fractions such as occur after micronisation processes. However, these processes do not necessarily result in the breakdown of beta-lactose, which may also occur in these treatment processes, and during the large-scale industrial grinding of lactose to a particle size range with a value of x50>10 μm. Thermodynamically unstable fractions such as beta-lactose, for example, even if they are only present on the surface of lactose, constitute a factor which may have a negative effect on the long-term and storage stability of an inhalable powder, for example.
Even after using special methods for recrystallising amorphous fractions of lactose, as described in the prior art (cf e.g. WO 92/18110 or WO 95/05805), particles are obtained which, in spite of recrystallisation of any amorphous fractions present, still show microstructuring on the particles, which can be equated with areas of increased surface energy.
The problem of the present invention is to provide a process by which lactose particles can be modified so that on the one hand (primarily on the surface) they have a highly crystalline texture of the thermodynamically most stable modification under normal conditions, i.e. alpha-lactose monohydrate, and the surfaces of the particles are such that they can be described as being extremely smooth and substantially free of any microstructure.